Delta opioid receptors (DORs) have been considered as a potential target to relieve pain conditions and depression and anxiety disorders. Physical pain is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals experience pain by various daily hurts and aches, and sometimes through more serious injuries or illnesses. For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.
Pain is a common reason for physician consultation. It is a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Diagnosis is based on characterizing pain in various ways, according to duration, intensity, type (dull, burning, throbbing or stabbing), source, or location in body. Usually pain stops without treatment or responds to simple measures such as resting or taking an analgesic, and it is then called ‘acute’ pain. But it may also become intractable and develop into a condition called chronic pain, in which pain is no longer considered a symptom but an illness by itself.
Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and lead to significant changes in a patient's personality, lifestyle, functional ability or overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed. 1996).
Current analgesic therapies are only poorly effective and are associated with significant side effects, especially concerning chronic conditions.
The impact of chronic pain can vary from mild discomfort to the worst pain imaginable, having a devastating effect on the sufferers and their families. The types of pain are many and varied and include lower back pain, arthritis (especially osteoarthritis), headache (including migraine), fibromyalgia, nerve damage (neuropathy), neurological disease (e.g. multiple sclerosis), and post-viral illness (e.g. shingles).
Other CNS-related diseases such as Alzheimer's and Parkinson's have a high prevalence of associated pain. The incidence of chronic pain increases with advancing and is associated with and potentiated by depressive illness and loss of sleep.
DORs have multiple roles in the central nervous system disorders beside pain, such as in depression, anxiety, epilepsy, and stress and in gastrointestinal disorders such as in diarrhea, postoperative ileus, ulceration and irritable bowel syndrome and in related inflammatory disorders such as in osteoarthritis and rheumatoid arthritis, and in others including respiratory, alcoholism and obesity/binge eating.
The identification of at least three different populations of opioid receptors (δ), (μ) and (κ) receptors is now well established and all three are apparent in both central and peripheral nervous systems of many species including man.
A recent survey of more than 45,000 people in 16 countries revealed that almost 1 in 5 of the European population suffers moderate or severe pain persisting for more than 6 months. Chronic pain, therefore, constitutes an enormous burden on national economies and patients' quality of life. Given the number of different chronic pain states, the patient population is extremely varied, although it is very likely to be skewed towards the upper age range with neuropathies and joint pain being particularly prominent. In institutionalized elderly patients for example, up to 80% report a current pain problem although a significant proportion receive inadequate analgesic therapy. There is, therefore, an urgent need for novel pain therapies that are effective over prolonged periods with low side-effect risk.
The commonly used opioids, such as, codeine, dihydrocodeine (for mild to moderate pain) and oxycodone, tramadol etc. (for severe pain) are either non-selective, acting on all three opioid receptor sub-types or somewhat μ receptor-biased and they produce the full range of both beneficial and unwanted effects.
The widespread distribution of opioid receptor subtypes in the CNS and peripheral tissues results in the associated side-effects of nausea, constipation, itching and danger of life-threatening respiratory depression, produced by mixed opioid ligands. The development of tolerance additionally limits their clinical efficacy.
The development of tolerance additionally limits their clinical efficacy. Meta-analysis-derived evidence regarding the clinical efficacy of traditional opioids and other commonly used analgesics in chronic pain states is weak or negative; amitriptyline (a first line analgesic for neuropathic pain) benefits less than 40% of patients and, only about one third of patients treated with gabapentin obtain significant relief. The currently available voltage-activated sodium channel blockers also have very limited efficacy and significant CNS and cardio toxicity risks.
This commonality offers the possibility that modifying the activity of individual targets, such as the δ-opioid receptor (DOR) will provide benefit in pain treatment.
Outline of Invention
Compounds of this invention show selective high potency for the DOR. Compounds of the invention deliver a widened therapeutic window, and have the potential, in contrast to existing analgesics delivering only moderate pain relief, to produce maintained analgesia in pain states with less risk of unwanted effects including respiratory depression and constipation.
Compounds of this invention will significantly expand treatment options for clinicians and increase the quality of life for a huge number of patients.
The present invention provides a compound of formula (I)
or pharmaceutically acceptable salts thereof
Wherein
R is selected from any one of

According to an aspect of the invention, a compound of formula I is

According to another aspect of the invention, a compound of formula I is

According to another aspect of the invention, a compound of formula I is

According to an aspect of the invention the compounds of formula I are used in pain therapy, such as treating acute pain and chronic pain.
Compounds of the invention are highly potent and will retain analgesic potency on repeated administration. Compounds of the invention will be useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, osteoarthritis, fibromyalgia, migraine, visceral pain, diabetic pain etc.
Compounds of the invention are equally useful for the treatment of depression and anxiety as for various types of pain conditions, as mentioned above.
Compounds of the invention are useful for the treatment of urinary incontinence, various mental illnesses, cough, lung edema, various gastro-intestinal disorders (irritable bowel syndrome, irritable bowel disease), spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts and organ transplants.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful as an analgesic agent for use during general anesthesia and monitored anesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, neuropeptide receptor blockers and other opioids.
Compounds of the invention can be used in combination therapy with other pain effective compounds.
Within the scope of the invention is the use of the compound of formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of compound according to the formula I above, is administered to a patient in need of such treatment.
A further aspect of the invention is a pharmaceutical composition comprising at least a compound of the formula I as an active ingredient, or a physiologically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Methods of Preparation
The compounds of formula (I) prepared as outlined in scheme 1.

Wherein R′CH═O is:

The following abbreviations have been used:
Dppf=(diphenylphosphino)ferrocene
HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate